Alternatives to currently used antimalarial drugs: in search of a magic bullet.
Alternatives to currently used antimalarial drugs: in search of a magic bullet.
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DOI：
10.1186/s40249-016-0196-8
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发表时间：
2016-11-04
影响因子：
8.1
通讯作者：
Shehab A
中科院分区：
文献类型：
--
作者：
Bhagavathula AS;Elnour AA;Shehab A
疟疾是许多非洲国家以及亚洲和南美洲部分地区发病率和死亡率的主要原因。近年来出现了抗击这种疾病的新方法，几种候选药物目前正在进行临床测试。然而，这些新药要投放市场还需要很长时间，特别是由于缺乏安全性和有效性数据。为了减轻疟疾负担，1999年成立了疟疾药物合资企业(MMV)，通过产业界和学术伙伴的合作开发新药。然而，自MMV启动以来(2000年)到目前为止，发表的各种临床前和临床研究没有集中综述。我们在全球抗疟疾药物组合中确定了有前景的方法，并强调了这些新分子的挑战和患者特有的担忧。我们讨论了不同的临床研究，重点是在过去五年的不同人体试验中对治疗疟疾的新药进行评估。药物KAE609和DDD107498仍在I期试验和临床前开发研究中进行评估。KAF156和DSM265等新型化合物的安全性和有效性需要进一步评估，特别是在孕妇身上使用。合成的非青蒿素臭氧化合物，如OZ277，对高寄生负荷的效力不足，引起了关注。基于氨基喹啉的支架，如铁喹是很有前途的，但应该与好的伙伴药物结合以增强疗效。AQ-13诱发心电事件，导致QT间期延长。他苯喹是唯一一种用于葡萄糖-6-磷酸脱氢酶缺乏症患者的新型抗复发支架，由于其溶血活性而引起了极大的关注。其他化合物，包括亚甲蓝(潜在的传输阻滞剂)和磷霉素(DXP还原异构酶抑制剂)，也是可用的，但不能用于儿童。在这个阶段，我们无法找到对抗疟疾的单一灵丹妙药。未来的研究应该侧重于有效的单剂分子，这些分子可以对抗疟疾的所有阶段，以防止传播。较新的药物也在疗效和安全性方面引起了担忧。总体而言，需要更多证据才能有效降低目前的疟疾负担。需要针对血液阶段的治疗策略，具有阻断传播的特性，以防止未来的耐药性。本文的在线版本(doi：10.1186/s40249-0160196-8)包含补充材料，授权用户可以使用。
Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data. To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners’ collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date. We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years. The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children. At this stage, we are unable to identify a single magic bullet against malaria. Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission. Newer medicines have also raised concerns in terms of efficacy and safety. Overall, more evidence is needed to effectively reduce the current malaria burden. Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance. The online version of this article (doi:10.1186/s40249-016-0196-8) contains supplementary material, which is available to authorized users.
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恶性疟原虫网状蛋白相关的衔接蛋白2的MU亚基在体外寄生虫对青蒿素和奎宁的反应调节。
影响因子：
4.9
作者：
Henriques G;van Schalkwyk DA;Burrow R;Warhurst DC;Thompson E;Baker DA;Fidock DA;Hallett R;Flueck C;Sutherland CJ
通讯作者：
Sutherland CJ
DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
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通讯作者：
Guy, R. Kiplin
影响因子：
5.8
作者：
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通讯作者：
Ginsburg, H
影响因子：
4.2
作者：
Jaudzems, Kristaps;Tars, Kaspars;Jirgensons, Aigars
通讯作者：
Jirgensons, Aigars
影响因子：
3.3
作者：
Bountogo, Mamadou;Zoungrana, Augustin;Muller, Olaf
通讯作者：
Muller, Olaf